The majority of PDAC cases in humans carry mutations in the KRAS gene. While oncogenic KRAS is sufficient to initiate the formation of pre-cancerous lesions in the pancreas, the development of invasive PDAC requires an accumulation of additional genetic and epigenetic alterations in other tumor susceptibility loci as well as changes in cytokine signaling. Inflammatory cytokines produced by the stroma and, more importantly, by the cancer cells themselves are important drivers for pancreatic cancer progression. Interleukin-6 (IL-6)-class cytokines are considered master regulators of cancer-associated inflammation and they all signal through specific ligand-receptor complexes that share the glycoprotein 130 (gp130) signal transducing subunit, which activates Janus kinases (JAKs) and their downstream Signal Transducers and Activators of Transcription (STATs). IL-6-class cytokines are responsible for the persistent activation of STAT3 in cancer cells, which is a prerequisite for the progression of KRAS-driven pancreatic neoplasms. Using a novel genetically engineered mouse model, we can demonstrate that JAK1, and not JAK2 as commonly believed, is crucial for the activation of STAT3. Given the importance of IL-6 and STAT3 in malignant transformation, our findings provide a sound rationale for elucidating a potentially pivotal role for JAK1 in pancreatic carcinogenesis. The immediate objectives of this proposal are to mechanistically define how JAK1/STAT3 signaling contributes to the genesis and progression of PDAC. To accomplish this goal, we will use human pancreatic cancer cells and a state-of- the-art genetically engineered mouse model of pancreatic cancer to determine the biological significance of JAK1 in pancreatic cancer progression (aim 1). After establishing that targeting JAK1 is sufficient to block the activation of STAT3 and prevent pancreatic cancer metastasis, we will perform genome-wide transcriptome analyses to ascertain and validate new targets of JAK1/STAT3 signaling in PDAC. To assist the development of pharmacological agents that specifically target JAK1, we will further define sets of downstream target genes that can be used as biomarkers for a successful inhibition of this particular signaling pathway in human pancreatic cancer cells (aim 2). In the final aim of this project, we will examine the biological significance of two JAK1 downstream targets, RUNX1 and c-FOS, in pancreatic cancer progression with particular emphasis on their suggested role in the regulation of factors for extra cellular matrix remodeling. In an effort towards clinical translation, we will test a recently developed JAK1 inhibitor to assess whether this agent is able to selectively block the activation of STAT3 and expression of validated downstream target genes in pancreatic cancer cells. In summary, this will be the first comprehensive study that addresses a specific role for JAK1 in adenocarcinoma, and the collective results of this project are expected to provide new and detailed insight into the molecular and biologically relevant functions of this important member of the Janus kinase family in pancreatic carcinogenesis.